γδ T cells mediate a requisite portion of a wound healing response triggered by cutaneous poxvirus infection

Abstract

Infection at peripheral sites, such as the skin, activates local innate immune defenses tasked with limiting spread of the pathogen while preserving tissue integrity. T cells bearing {gamma}{delta} T Cell Receptors (TCR), which comprise multiple phenotypically distinct subtypes of cells, reside in normal skin, where they shape immunity to cutaneous infection, prior to onset of an adaptive immune response by conventional {beta} CD4+ (TCD4+) and CD8+ (TCD8+) T cells. The mechanisms used by {gamma}{delta} T cells to control virus replication and tissue pathology following cutaneous infection are unknown, so we examined the role of {gamma}{delta} T cells in the response to cutaneous infection with vaccinia virus (VACV). Resident {gamma}{delta} T cells in the skin expanded and combined with recruited {gamma}{delta} T cells to control the pathology observed after cutaneous VACV infection. However, we observed no defect in control of local virus replication or increased systemic spread in mice lacking {gamma}{delta} T cells, despite induction of a cytolytic response in a specialized subset of resident {gamma}{delta} T cells. While examining {gamma}{delta} T cell-mediated control of tissue pathology following cutaneous VACV infection, we identified a unique wound healing signature associated with cutaneous virus infection that has features that are common to, but also features that antagonize, the sterile cutaneous wound healing response. Typically, tissue repair is thought to occur only after clearance of a pathogen, but the viral wound healing signature was evident prior to the peak of virus replication in the skin. Resident and recruited {gamma}{delta} T cells contributed to this wound healing signature through induction of multiple cytokines and growth factors required for efficient wound closure. Therefore, {gamma}{delta} T cells are early mediators of the wound healing response following cutaneous virus infection and are likely important in maintenance of skin barrier function and prevention of secondary bacterial infection. Author Summary{gamma}{delta} T cells resident in the skin are among the first immune cell types positioned to be able to respond to a virus infection of the skin. Therefore, it was assumed that these cells in the skin play a role similar to their role after widespread infection throughout the body, namely to kill virus infected cells and slow virus replication and spread. However, we found no role for {gamma}{delta} T cells in control of virus replication after infection of the skin. Rather, the {gamma}{delta} T cells functioned as a critical component of a previously unrecognized wound healing response that is started early after virus infection of the skin, and occurs at the same time as the immune response that aims to clear the virus. This study is the first to describe both the early wound healing response after virus infection, and the role of {gamma}{delta} T cells in that response, and this information could allow manipulation of this response to decrease secondary bacterial infection and change scarring after virus skin infections.